pertuzumab
Sources réglementaires consultées
Indications approuvées
- En association avec trastuzumab et docétaxel, cancer du sein métastatique HER2+ de l’adulte sans traitement anti-HER2 ni chimiothérapie antérieurs pour la maladie métastatique.
- En association avec trastuzumab et chimiothérapie, traitement néoadjuvant du cancer du sein HER2+ de l’adulte localement avancé, inflammatoire ou précoce de plus de 2 cm ou avec ganglions positifs ; et traitement adjuvant du cancer du sein précoce HER2+ à haut risque de récidive.
Contre-indications
Absolues
- Hypersensibilité connue au pertuzumab ou à ses excipients.
Mises en garde cliniques
- Mise en garde encadrée · Il peut provoquer une dysfonction ventriculaire gauche et une insuffisance cardiaque. Évaluer la FEVG avant et pendant le traitement et suspendre ou arrêter selon le tableau propre à l’indication. — FDA SPL, PERJETA set_id 17f85d17-ab71-4f5b-9fe3-0b8c822f69ff
- Mise en garde encadrée · Il peut provoquer une mort embryofœtale, un oligohydramnios et une altération du développement rénal fœtal. Vérifier la grossesse avant le traitement. — FDA SPL, PERJETA set_id 17f85d17-ab71-4f5b-9fe3-0b8c822f69ff
- Mise en garde majeure · Il peut provoquer des réactions à la perfusion et une hypersensibilité graves ou mortelles, notamment une anaphylaxie et un angio-œdème. Surveiller, ralentir ou interrompre la perfusion et arrêter en cas d’anaphylaxie sévère. — FDA SPL, PERJETA set_id 17f85d17-ab71-4f5b-9fe3-0b8c822f69ff
Effets indésirables
Communs (≥1%)
diarrhée · alopécie · neutropénie · nausées · fatigue · éruption cutanée · neuropathie périphérique · vomissements
Rares mais graves
insuffisance cardiaque · réaction mortelle à la perfusion · anaphylaxie
Grossesse et allaitement
Il peut provoquer une toxicité fœtale. Vérifier la grossesse avant le traitement et utiliser une contraception efficace pendant le traitement et pendant 7 mois après la dernière dose. Pour l’allaitement, mettre en balance les bénéfices, le besoin clinique maternel et le risque potentiel, en tenant compte de la période d’élimination du trastuzumab de 7 mois.
Bibliographie récente (PubMed)
Trastuzumab deruxtecan has shown efficacy in patients with previously treated human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic breast cancer. The efficacy and safety of trastuzumab deruxtecan in patients with no previous therapy for HER2-positive advanced or metastatic breast cancer are unclear. We conducted a phase 3 trial involving patients with HER2-positive advanced or metastatic breast cancer and no previous chemotherapy or HER2-directed therapy for metastatic disease. Patients were randomly assigned in a 1:1:1 ratio to receive trastuzumab deruxtecan plus pertuzumab; trastuzumab deruxtecan plus placebo; or a taxane, trastuzumab, and pertuzumab (THP). The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included objective response, duration of response, and safety. For this prespecified interim analysis, data for trastuzumab deruxtecan plus pertuzumab and for THP are reported; data for trastuzumab deruxtecan plus placebo remain blinded until the final analysis of progression-free survival. At the data-cutoff date (February 26, 2025), the median progression-free survival was 40.7 months with trastuzumab deruxtecan plus pertuzumab (383 patients) and 26.9 months with THP (387 patients) (hazard ratio for progression or death, 0.56; 95% confidence interval [CI], 0.44 to 0.71; P<0.00001 [P-value boundary for superiority, 0.00043]). The incidence of a confirmed response was 85.1% with trastuzumab deruxtecan plus pertuzumab and 78.6% with THP (complete responses in 15.1% and 8.5%, respectively), with a median duration of response of 39.2 months and 26.4 months. Safety was consistent with the known profiles of the individual treatments. The incidence of grade 3 or higher adverse events was 63.5% with trastuzumab deruxtecan plus pertuzumab and 62.3% with THP; the most common were neutropenia, hypokalemia, and anemia with trastuzumab deruxtecan plus pertuzumab and neutrope
Neoadjuvant standard-of-care for HER2-positive early-stage breast cancer is trastuzumab + pertuzumab with polychemotherapy; however, existing regimens have high toxicity burdens and suboptimal outcomes. DESTINY-Breast11 assessed efficacy and safety of neoadjuvant trastuzumab deruxtecan (T-DXd) alone or followed by paclitaxel + trastuzumab + pertuzumab (THP) versus dose-dense doxorubicin + cyclophosphamide (ddAC) followed by THP for high-risk (≥cT3cN0 or cT0-4cN1-3) HER2-positive disease. This open-label, phase III trial (147 sites, 18 countries) randomised adults 1 : 1 : 1 to T-DXd (×8 cycles), T-DXd-THP (4 + 4 cycles), or ddAC-THP (4 + 4 cycles). T-DXd-alone arm enrolment closed early following the Independent Data Monitoring Committee recommendation. The primary endpoint was pathological complete response (pCR; ypT0/is ypN0; intent-to-treat population). Secondary endpoints included event-free survival (EFS; intent-to-treat population) and safety (safety analysis set). Between 25 October 2021 and 12 March 2025, 286 (T-DXd), 321 (T-DXd-THP), and 320 (ddAC-THP) female patients were randomised. pCR rates were 43.0% (T-DXd, n = 123), 67.3% (T-DXd-THP, n = 216), and 56.3% (ddAC-THP, n = 180). T-DXd-THP versus ddAC-THP absolute pCR rate difference was 11.2% [95% confidence interval (CI), 4.0% to 18.3%, P = 0.003], with benefit in hormone receptor (HR)-positive [61.4% (n/N = 145/236) versus 52.3% (n/N = 123/235); difference in pCR (ΔpCR) 9.1% (95% CI 0.2% to 17.9%)] and HR-negative [83.1% (n/N = 69/83) versus 67.1% (n/N = 57/85); ΔpCR 16.1% (95% CI 3.0% to 28.8%)] subgroups. Median EFS (T-DXd-THP versus ddAC-THP, maturity 4.5%) hazard ratio was 0.56 (95% CI 0.26 to 1.17). Grade ≥3 adverse events (AE; T-DXd, 22.6% (n = 64); T-DXd-THP, 37.5% (n = 120); ddAC-THP, 55.8% (n = 174)], serious AE [T-DXd, 10.2% (n = 29); T-DXd-THP, 10.6% (n = 34); ddAC-THP, 20.2% (n = 63)], and all-grade left-ventricular dysfunction [T-DXd, 0.7% (n = 2); T-DXd-THP, 1.3% (n = 4); ddAC-THP, 6.1% (n
An improvement in progression-free survival was shown with trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer in the progression-free survival interim analysis of the DESTINY-Breast03 trial. The aim of DESTINY-Breast03 was to compare the efficacy and safety of trastuzumab deruxtecan versus trastuzumab emtansine. This open-label, randomised, multicentre, phase 3 trial was done in 169 study centres in North America, Asia, Europe, Australia, and South America. Eligible patients were aged 18 or older, had HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab and a taxane, had an Eastern Cooperative Oncology Group performance status 0-1, and at least one measurable lesion per Response Evaluation Criteria in Solid Tumours version 1.1. Patients were randomly assigned (1:1) to receive trastuzumab deruxtecan 5·4 mg/kg or trastuzumab emtansine 3·6 mg/kg, both administered by intravenous infusion every 3 weeks. Randomisation was stratified by hormone receptor status, previous treatment with pertuzumab, and history of visceral disease, and was managed through an interactive web-based system. Within each stratum, balanced block randomisation was used with a block size of four. Patients and investigators were not masked to the treatment received. The primary endpoint was progression-free survival by blinded independent central review. The key secondary endpoint was overall survival and this prespecified second overall survival interim analysis reports updated overall survival, efficacy, and safety results. Efficacy analyses were performed using the full analysis set. Safety analyses included all randomly assigned patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03529110. Between July 20, 2018, and June 23, 2020, 699 patients were screened for eligibility, 524 of whom were enrolled and randomly assigned to receive trastuzumab
The HER2CLIMB-05 study (ClinicalTrials.gov identifier: NCT05132582) is investigating the efficacy and safety of adding tucatinib to trastuzumab and pertuzumab as first-line (1L) maintenance therapy in patients with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC). Patients with centrally confirmed HER2+ MBC without evidence of progression post induction therapy and no or asymptomatic brain metastases (BM) were enrolled. Patients were randomly assigned 1:1 to tucatinib (300 mg) or placebo twice a day combined with trastuzumab/pertuzumab. The primary end point is investigator-assessed progression-free survival (PFS); secondary end points include overall survival (OS), PFS per blinded independent central review, CNS-PFS, and safety. Between March 2022 and July 2024, 654 patients were randomly assigned to tucatinib (n = 326) and placebo (n = 328) arms. All patients were female (median age, 54 years), 69.3% had de novo MBC, 52.6% were hormone receptor-positive, and 12.4% had presence/history of baseline BM. In this primary analysis, PFS was statistically significantly improved with addition of tucatinib versus placebo (hazard ratio, 0.641 [95% CI, 0.514 to 0.799]; P < .0001; median PFS: 24.9 v 16.3 months); a PFS benefit was seen regardless of the presence/absence of BM or hormone receptor status. OS data remain immature. The most common treatment-emergent adverse events (TEAEs) in the tucatinib arm were diarrhea (72.7%), nausea (33.1%), and elevated liver enzymes (ALT: 28.2%; AST: 25.8%), of which 6.1%, 0.9%, 13.5%, and 7.1%, respectively, were grade ≥3. In the tucatinib arm, 13.5% discontinued tucatinib because of TEAEs. Tucatinib addition to trastuzumab and pertuzumab demonstrated improvement in PFS with no new safety signals identified and may be an option for 1L maintenance therapy in patients with HER2+ MBC.
Breast cancer is currently the most commonly occurring cancer globally. Among breast cancer cases, the human epidermal growth factor receptor 2 (HER2)-positive breast cancer accounts for 15% to 20% and is a crucial focus in the treatment of breast cancer. Common HER2-targeted drugs approved for treating early and/or advanced breast cancer include trastuzumab and pertuzumab, which effectively improve patient prognosis. However, despite treatment, most patients with terminal HER2-positive breast cancer ultimately suffer death from the disease due to primary or acquired drug resistance. The prevalence of aberrantly activated the protein kinase B (AKT) signaling in HER2-positive breast cancer was already observed in previous studies. It is well known that p-AKT expression is linked to an unfavorable prognosis, and the phosphatidylinositol-3-kinase (PI3K)/AKT pathway, as the most common mutated pathway in breast cancer, plays a major role in the mechanism of drug resistance. Therefore, in the current review, we summarize the molecular alterations present in HER2-positive breast cancer, elucidate the relationships between HER2 overexpression and alterations in the PI3K/AKT signaling pathway and the pathways of the alterations in breast cancer, and summarize the resistant mechanism of drugs targeting the HER2-AKT pathway, which will provide an adjunctive therapeutic rationale for subsequent resistance to directed therapy in the future.